Abstract

Background

The typical effect of antibiotic initiation on the international normalized ratio (INR) in a real-world, stable warfarin population has not been adequately described. In addition, the influence of acute illness on the risk of excessive anticoagulation is not known.

Methods

This retrospective, longitudinal cohort study evaluated patients who received stable warfarin therapy between January 1, 2005 and March 31, 2011. The protocol for patients receiving warfarin and initiating antibiotic therapy during the study time-frame was to continue the warfarin dose unchanged and measure an INR within 3 to 7 days. Patients who purchased an antibiotic (antibiotic group) were compared to those purchasing a warfarin refill (stable controls) and patients with upper respiratory infection who did not purchase an antibiotic (sick controls). Primary outcomes included the mean INR change between the last INR prior to study inclusion (pre-index INR) and the first follow-up INR as well as the percentage of patients with a follow-up INR ≥ 5.0. The influence of interaction mechanism on the risk of a follow-up INR ≥ 5.0 was evaluated and predictors of a follow-up INR ≥ 5.0 were identified.

Results

A total of 5905 (49.0%), 5579 (46.2%), and 570 (4.8%) patients were included in the antibiotic, stable control, and sick control groups, respectively. The mean age was 68.3 years and the median pre-index INR was 2.5 (IQR 2.2-2.9). The mean change in INR was greater in the antibiotic group compared to the stable and sick control groups (both p< 0.05) but the increase was not clinically relevant (i.e., mean increase was less than 0.1 INR units). There were 3.2%, 2.6%, and 1.2% of patients with a follow-up INR ≥ 5.0 in the antibiotic, sick, and stable groups respectively (antibiotics v. stable and sick v. stable p<0.001; antibiotics v. sick p=0.434). Antibiotics interfering with warfarin metabolism were more likely to result in a follow-up INR ≥ 5.0 (9.6%) than those disrupting Vitamin K synthesis (3.1%) and those without a known interaction with warfarin (2.1%) (p<0.01) (Table). Antibiotic use, acute illness, cancer diagnosis, elevated baseline INR, and female sex predicted a follow-up INR ≥ 5.0.

Table

Thirty-Day Outcomes by Antibiotic and Interaction Mechanism

AntibioticFollow-Up INR ≥ 5.01 (n, %)P-Value2Follow-Up INR > 3.53 (n, %)P-Value2
No Interaction Reported (n=660) 14, 2.1% <0.001 95, 14.4% <0.001 
  Cefuroxime axetil (n=65) 0, 0.0% 0.407 13, 20.0% 0.029 
  Clindamycin (n=269) 6, 2.2% 0.997 42, 15.6% 0.028 
  Nitrofurantoin (n=189) 6, 3.2% 0.378 22, 11.6% 0.921 
  Trimethoprim (n=137) 2, 1.5% 0.772 18, 13.1% 0.523 
Disruption of Vitamin K Synthesis (n=5046) 158, 3.1% <0.001 663, 13.1% <0.001 
  Amoxicillin (n=1036) 13, 1.3% 0.026 103, 9.4% 0.119 
  Amoxicillin /clavulanate (n=397) 11, 2.8% 0.461 50, 12.6% 0.451 
  Azithromycin (n=523) 20, 3.8% 0.012 100, 19.1% <0.001 
  Cephalexin (n=901) 17, 1.9% 0.464 90, 10.0% 0.162 
  Ciprofloxacin (n=981) 42, 4.3% <0.001 109, 11.1% 0.756 
  Doxycycline (n=724) 25, 3.5% 0.022 115, 15.9% <0.001 
  Levofloxacin (n=169) 9, 5.3% 0.006 26, 15.4% 0.102 
  Moxifloxacin (n=218) 20, 9.2% <0.001 59, 27.1% <0.001 
  Penicillin (n=97) 1, 1.0% 0.727 11, 11.3% 0.982 
Inhibition of CYP Metabolism (n=199) 19, 9.6% <0.001 48, 24.1% <0.001 
  Fluconazole (n=48) 6, 12.5% <0.001 16, 33.3% <0.001 
  Metronidazole (n=67) 7, 10.5% <0.001 16, 23.9% 0.001 
  TMP/SMX (n=84) 6, 7.1% 0.002 16, 19.1% 0.027 
AntibioticFollow-Up INR ≥ 5.01 (n, %)P-Value2Follow-Up INR > 3.53 (n, %)P-Value2
No Interaction Reported (n=660) 14, 2.1% <0.001 95, 14.4% <0.001 
  Cefuroxime axetil (n=65) 0, 0.0% 0.407 13, 20.0% 0.029 
  Clindamycin (n=269) 6, 2.2% 0.997 42, 15.6% 0.028 
  Nitrofurantoin (n=189) 6, 3.2% 0.378 22, 11.6% 0.921 
  Trimethoprim (n=137) 2, 1.5% 0.772 18, 13.1% 0.523 
Disruption of Vitamin K Synthesis (n=5046) 158, 3.1% <0.001 663, 13.1% <0.001 
  Amoxicillin (n=1036) 13, 1.3% 0.026 103, 9.4% 0.119 
  Amoxicillin /clavulanate (n=397) 11, 2.8% 0.461 50, 12.6% 0.451 
  Azithromycin (n=523) 20, 3.8% 0.012 100, 19.1% <0.001 
  Cephalexin (n=901) 17, 1.9% 0.464 90, 10.0% 0.162 
  Ciprofloxacin (n=981) 42, 4.3% <0.001 109, 11.1% 0.756 
  Doxycycline (n=724) 25, 3.5% 0.022 115, 15.9% <0.001 
  Levofloxacin (n=169) 9, 5.3% 0.006 26, 15.4% 0.102 
  Moxifloxacin (n=218) 20, 9.2% <0.001 59, 27.1% <0.001 
  Penicillin (n=97) 1, 1.0% 0.727 11, 11.3% 0.982 
Inhibition of CYP Metabolism (n=199) 19, 9.6% <0.001 48, 24.1% <0.001 
  Fluconazole (n=48) 6, 12.5% <0.001 16, 33.3% <0.001 
  Metronidazole (n=67) 7, 10.5% <0.001 16, 23.9% 0.001 
  TMP/SMX (n=84) 6, 7.1% 0.002 16, 19.1% 0.027 
1

- Overall rate of follow-up INR ≥ 5.0 among all antibiotics is 3.2%

2

– P-value for specific antibiotic compares against all other antibiotics; P-value for interaction mechanism group compares against other 2 mechanism groups

3

- Overall rate of follow-up INR > 3.5 among all antibiotics is 13.7%

- p<0.01 between No Interaction Reported & Inhibition of CYP Metabolism groups

- p<0.01 between Disruption of vitamin K Synthesis & Inhibition of CYP Metabolism groups

CYP – cytochrome P450, TMP/SMX – trimethoprim and sulfamethoxazole

Conclusion

In the absence of antibiotics, acute illness alone increases the risk of excessive anticoagulation in previously stable warfarin patients. The risk of an INR ≥ 5.0 was greatest among antibiotics interfering with warfarin metabolism. In addition to antibiotics and acute illness, patients with cancer, elevated baseline INR, and females were most susceptible to excessive anticoagulation.

Disclosures:

Hylek:Bayer: Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Daiichi Sankyo: Consultancy; Johnson and Johnson: Consultancy; Pfizer: Consultancy. Garcia:Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy; Boehringer Ingelheim: Consultancy; Daiichi Sankyo: Consultancy; Janssen: Consultancy; Roche Diagnostics: Consultancy; CSL Behring: Consultancy. Crowther:Asahi Kasai: Membership on an entity’s Board of Directors or advisory committees; Baxter: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; CSL Behring: Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Merck: Consultancy; Octapharma: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Viropharma: Membership on an entity’s Board of Directors or advisory committees.

Author notes

*

Asterisk with author names denotes non-ASH members.

This icon denotes a clinically relevant abstract